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Neurotransmission - Biochem


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Otto Loewi frog heart experiment
In 1921 Austrian/German biologist Otto Loewi discovered the first neurotransmitter. His experiment involved placing 2 frog hearts in separate saline-filled chambers. One heart was left connected to the animal’s vagus nerve. He stimulated the vagus nerve, which slowed down the connected heart. He then repeated the stimulation while pumping the fluid surrounding the stimulated heart into the chamber containing the other heart. To his surprise, the other heart also slowed down, suggesting that something in the fluid (which he called “vagusstoff”) had caused the 2nd heart to slow down.

This substance was subsequently identified as Acetylcholine, and in 1936 Loewi received the Nobel Prize for this work.
The Synapse
The site of action of neurotransmitters is the synapse (from the Greek word meaning to clasp together). The synapse is a minute space between the terminals of one neuron (referred to as the presynaptic cell), and another neuron (known as the postsynaptic cell).
The actual presynaptic site is an enlargement of the presynaptic neuron terminal called a button or bouton that forms a very close contact with downstream cells. This terminal can form synapses on the dendrites, cell body or axon of the postsynaptic cell.
The life cycle of transmitter agents entails
(1) neurotransmitter synthesis, (2) packaging into vesicles, (3) fusion of vesicles resulting in neurotransmitter release, and (4) activation of postsynaptic receptors. Neurotransmitters are then removed from the synaptic cleft (5). In many cases, the neurotransmitter and/or a breakdown product is reused for neurotransmitter synthesis.
Properties of Neurotransmitters
(classification system)
Synthesized (made) locally, within the neuron
Stored locally
Released into the synapse
Binds to receptors on postsynaptic cells
Inactivated after a brief time
discrete steps in neurotransmission have been identified. Each step represents an opportunity to affect neurotransmission with pharmacological agents.
1.Axonal transport to terminal
2.Action potential generation
3.Terminal synthesis and release
4.Catabolism in extracellular space and glia
5.Postsynaptic receptor response
6. Postsynaptic organelle response to receptor activation
7.Postsynaptic nuclear genetic expression changes
8.Generation of postsynaptic action potential
9. Autoreceptors
Known and Suspected Neurotransmitters (name 4)
Amino Acids
Trophic factors
Synthesis =Choline + Acetyl CoA
-Released from presynaptic vesicles following calcium influx into terminal
-Hydrolyzed after release by acetylcholinesterase
Two classes of ACh receptors:
nicotinic (responsive to nicotine) and muscarinic (responsive to an alkaloid from toadstool mushrooms)
Acetyl coenzyme A synthesized in
Ach implicated in
(name 4)
Myasthenia gravis
Claustridium Botulinum: food poisoning caused by toxins produced by bacteria can cause death by paralyzing muscles used in respiration
Botox: used by plastic surgeons to temporarily block nerve impulses to muscles causing wrinkles
Smokers for the most part aren’t interested in tobacco’s flavor or the smoke. They are simply trying to get nicotine into their brains, where it:
A. locks ACh channels open
B. inhibits MAO (monoamine oxidase), increasing dopamine’s action at postsynaptic cells.
Major Excitatory Amino Acid transmitters
Major Inhibitory Amino Acid transmitters
-GABA (g-aminobutyric acid)
Main inhibitory transmitter

Valium/Diazepam (benzodiazepine; increases action of GABA atGABAa receptors)

Anticonvulsants (GABA agonists)

-stroke (excess Glu=toxic to brain cells)
Parkinson’s (DA basal ganglia deficit)
Schizophrenia (excess frontal lobe DA)
Generally inhibitory
Reward circuits
Nicotine, cocaine, heroin, alcohol all increase dopamine
Synthesis, packaging, secretion, and removal of peptide neurotransmitters
These NT as well as the enzymes that modify their precursors, are synthesized in the cell body. Enzymes and propeptides are packaged into vesicles in the Golgi apparatus. During fast axonal transport of these vesicles to the nerve terminals. The enzymes modify the propeptides to produce one or more neurotransmitter peptides. After vesicle fusion and exocytosis, the peptides diffuse away and are degraded by proteolytic enzymes.
Synthesis, packaging, secretion, and removal of small-molecule neurotransmitters
1) synthesized at nerve terminals
2)enzymes necessary for neurotransmitter synthesis are made in the cell body of the presynaptic cell and are transported down the axon by slow axonal transport
3)Precursors are taken up into the terminals by specific transporters, and neurotransmitter synthesis and packaging takes place within nerve endings.
4) After vesicle fusion and release the neurotransmitter may be enzymatically degraded. The reuptake of the NT (or it's metabolites) starts another cycle of synthesis, packaging, release, and removal
seratonin involved in
Peptides NTs
Modulate action of other neurotransmitters
Endocannabinoids NTs
1. stress hormones cause release of cannabinoids from hypothalamic neurons

2. Oxytocin cells release cannabinoids

3. Retrograde messenger that modulates neurotransmission

4. Involved in spinal cord motor pattern regulation
“endogenous morphine
-similar structure to opiates heroin, opium, morphine

implicated in:
-reward, pleasure
three notable points RE: major neurotransmitter systems
1. general brainstem/midbrain-to-forebrain/cortex projection pattern
2. The similarity of the rat brain to the human brain.
3. The common pathways through the MFB.
transmembrane proteins with extracellular binding site
types of receptors
A. Ligand gated (ionotropic)B. G-protein-linked (metabotropic)
C. Steroid
D. Tyrosine kinase
Structure of receptor protein includes ___ transmembrane domains.
______ receptors open/close, affecting ion flux across the membrane
Ligand gated
___________ also can affect ion channel opening, gene expression changes, neurotransmitter synthesis and release.
2nd messenger gated receptors
Ligand gated receptors
affect ion channel opening/closing in one of two ways. They can be ion channels themselves, or they can be closely linked to ion channels. Thus, channel conformational changes happen very quickly and are of relatively short duation.
Signal Transduction and Second Messengers
Communication continues intracellularly after neurotransmitters (1st messenger) act at receptors.
Effects may last on the order of ms to many minutes
Signal Transduction and Second Messengers : Norepinephrine
NE binds to receptors receptors bind to G proteins G-protein causes adeynyl cyclase to convert ATP to cAMP. cAMP can have many effects:
1. Change ion channel permeability
2. Nuclear gene expression
3. Alter Neurotransmitter synthesis
The _______ construction of the cell membrane has important implications for the operation of receptors. The phospholipid molecules are hydrophilic and the receptor molecules are embedded in the membrane.
lipid bilayer
Second messenger signalling systems use _______ to amplify the initial “first messenger” signal.
G proteins
Diversity of G Protein-Coupled Receptor Signal Transduction Pathways
Receptors coupled to heterotrimeric GTP-binding proteins (G proteins) are integral transmembrane proteins that transduce extracellular signals to the cell interior. G protein-coupled receptors exhibit a common structural motif consisting of seven membrane spanning regions. Receptor occupation promotes interaction between the receptor and the G protein on the interior surface of the membrane. This induces an exchange of GDP for GTP on the G protein  subunit and dissociation of the  subunit from the  heterodimer. Depending on its isoform, the GTP- subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channel or kinase function.
Neurotransmitters are either synthesized relatively directly from _______ (e.g. tryptophan/serotonin) or indirectly (e.g. glucose/GABA).
dietary sources/
synthesis of dopamine
the amino acid tyrosine is converted to DOPA, which is converted to dopamine, which is then converted to norepinephrine, given the presence of the appropriate enzymes.
L-Dopa is given therapeutically to increase dopamine levels in an attempt to treat symptoms of _________.
Parkinson’s disease
Neurotransmitter Inactivation
Diffusion Degradation Glia Reuptake
Several factors come into play once a neurotransmitter is released into the synapse. “Leftover” transmitter, that is, not bound to receptors, can be ___________, or it can be _____________.
metabolized in the synapse/ taken up by glia and/or neurons and either metabolized or reused for synthesis

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